Field of the Invention
The present invention relates to a pharmaceutical composition comprising a medium system and n-butylidenephthalide which is stable in the medium system. Particularly, the present invention relates to a pharmaceutical composition with n-butylidenephthalide that can be administrated by intranasal administration and is effective in the treatment of malignant brain tumor.
Descriptions of the Related Art
Astrocyroma, anaplastic astrocytoma and glioblastoma multiforme (GBM) are common malignant brain tumors of adults, among them, glioblastoma multiforme is the most common, most malignant and most invasive one.
Malignant brain tumor is a highly invasive disease with a very high death rate. The effective treatment method for this disease is still an unmet medical need. Currently there are three types of treatment, i.e., surgery, radiotherapy and chemotherapy. Surgery can eliminate most of the tumor, but it will hurt the other normal brain tissue and thereby affect the patient's athletic ability and linguistic ability. Radiotherapy can partially eliminate the tumor, but also affect the surrounding normal tissue cells. Chemotherapy usually fails to provide a significant therapeutic effect because of the blood-brain barrier (BBB) problem, significant toxic side effects and drug resistance. Intranasal administration is a new and non-invasive administration route and therefore can reduce the risk of infection. Once a drug being administrated via nasal cavity, it can be rapidly absorbed through the nasal mucosa to generate desired efficacy without being affected by the liver first-pass metabolism. Furthermore, the drug absorbed through the nasal mucosa can easily pass through the blood-brain barrier and directly reach the central nervous system, and thus the toxicity effect can be reduced.
N-butylidenephthalide (BP) is a potential new drug for the treatment of malignant tumors, which is derived from the extract of Angelica sinensis. N-butylidenephthalide has a boiling point of 139° C. to 142° C. (5 mmHg) and thus is oil like under normal conditions. It is known that n-butylidenephthalide is effective in the treatment of various cancers including glioblastoma multiforme and mammary cancer. Furthermore, latest researches reveal that n-butylidenephthalide is effective in inhibiting the autophagy of motor neurons. For instance, US 2014/0045765 A1 discloses that n-butylidenephthalide and its metabolic products are effective in inhibiting the autophagy of motor neurons and can be used for used for curing amyotrophic lateral sclerosis (ALS).
Unfortunately, BP is hydrophobic compound and not soluble in water. Such a hydrophobic feature of n-butylidenephthalide strictly limits its uses as a formulation for oral administration, injection and/or intranasal administration, and restricts its clinical applications and animal studies wherein light animals such as rats are used in the studies.
Therefore, a dosage form of n-butylidenephthalide in which n-butylidenephthalide is soluble or stable is desired in the art so as to enhance the bioavailability of n-butylidenephthalide and to facilitate the transportation and/or delivery as well as the pre-clinical researches of n-butylidenephthalide. The present invention is an achievement developed in view of the above needs, which applies a medium system to stabilize n-butylidenephthalide and enhance its efficacy.